ORGANIC LETTERS
Stereoselective Synthesis of cis-2, 5-Disubstituted THFs: Application to Adjacent Bis-THF Cores of Annonaceous Acetogenins
2012 Vol. 14, No. 4 1054–1057
Hiromichi Fujioka,* Ryota Maehata, Shintaro Wakamatsu, Kenji Nakahara, Tatsuya Hayashi, and Tomohiro Oki Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871 Japan
[email protected] Received December 22, 2011
ABSTRACT
The iodocyclization of γ,δ-unsaturated alcohols in the presence of a silyl enol ether produced cis-2,5-disubstituted tetrahydrofurans in one pot via siloxy intermediates. N-Iodosuccinimide (NIS) effectively worked as an activator of the double bonds in the substrates and the silyl enol ether. Application to an expedient synthesis of the adjacent bis-tetrahydrofuran core of Annonaceous acetogenins with a cis/threo/cis relative stereochemistry is also described.
2,5-Disubstituted tetrahydrofurans (THFs) are found in many biologically active molecules including Annonaceous acetogenins,1 polyether antibiotics,2 macrodiolides,3 and others. For the preparation of such valuable skeletons, several elegant approaches have already been developed by many synthetic chemists.4 Among them, the electrophilic halocyclization of γ,δ-unsaturated alcohols is an attractive method to construct 2,5-disubstituted THF ring systems because the starting alcohols are easily prepared5 and the halogenated product lends itself to further useful synthetic (1) (a) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504. (b) Bermejo, A.; Figadere, B.; Zafra-Polo, M.-C.; Barrachina, I.; Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269. (2) Faul, M. M.; Huff, B. E. Chem. Rev. 2000, 100, 2407. (3) Kang, E. J.; Lee, E. Chem. Rev. 2005, 105, 4348. (4) (a) Harmange, J.-C.; Figadere, B. Tetrahedron: Asymmetry 1993, 4, 1711. (b) Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261. (c) Jalce, G.; Franck, X.; Figadere, B. Tetrahedron: Asymmetry 2009, 20, 2537. (5) For the preparation of some γ,δ-unsaturated alcohols, see references in the Supporting Information. (6) (a) Wiley, A. R.; Harris, T. W.; Brungardt, C.; Marx., M. J. Med. Chem. 1982, 25, 121. (b) Baldwin, S. W.; McIver, J. M. J. Org. Chem. 1987, 52, 322. (c) Miura, K.; Hondo, T.; Okajima, S.; Hosomi, A. Tetrahedron Lett. 1996, 37, 487. (d) Harrowven, C. D.; Sibley, E. M. G. Tetrahedron Lett. 1999, 8299. 10.1021/ol203425p r 2012 American Chemical Society Published on Web 02/08/2012
transformations. In general, the halocyclization of the γ,δ-unsaturated alcohols favorably produces trans-2, 5-THFs because trans isomers are thermodynamically more stable than cis isomers.6,7 However, cis-2,5-THF moieties widely occur in many natural products. In the early 1980s, Bartlett et al. reported the stereoselective iodocyclization of benzyloxy derivatives leading to cis-2,5-THFs.7 They showed that steric repulsion between the protective group on the hydroxyl function and the substituents at the 2 or 5 positions were critical for the cis-selective fashion. Other groups also reported synthesis of cis-2,5-THFs based on a similar strategy,8 although protection of the hydroxyl group was necessary. The preparation of protected alcohols is usually conducted under acidic or basic conditions. Aiming at complex natural product synthesis, the regiocontrolled (7) Rychnovsky, S. D.; Bartlett, P. A. J. Am. Chem. Soc. 1981, 103, 3963. (8) (a) Marek, I.; Lefranc-ois, J.-M.; Normant, J.-F. Tetrahedron Lett. 1992, 33, 1747. (b) Zhang, H.; Weifang, S.; Ruan, Z.; Mootoo, D. R. Tetrahedron Lett. 1995, 36, 649. (c) Ruan, Z.; Dabideen, D.; Blumenstein, M.; Mootoo, D. R. Tetrahedron 2000, 56, 9203. (d) Kim, S.-W.; Choi, M.-S.; Park, G.; Kim, Y. S.; Cho, S. G. Bull. Korean Chem. Soc. 2001, 22, 626.
protection of poly hydroxyl compounds is sometimes problematic. Furthermore, a wide substrate scope has also not been fully examined to date. In this paper, we describe a novel diastereoselective iodocylization to give cis-2,5-THFs from the γ,δ-unsaturated alcohols in a one-pot procedure using silyl enol ethers for the in situ silylation. For the development of an alternative approach to cis2,5-THFs, we proposed that halogenating reagents serve as an activator of silyl enol ethers to convert the γ, δ-unsaturated alcohols into the siloxy derivatives and the successive intramolecular halocyclization, thus yielding cis-2,5-THFs in one operation.9 We examined the reaction conditions using 1a as a model substrate to demonstrate our concept (Table 1). First, the iodocyclization of 1a with N-iodosuccinimide (NIS) (2.5 equiv) in dichloromethane produced the trans isomer 3a as a major product, as expected (entry 1). The iodocyclization in the presence of various types of trimethylsilyl (TMS) enol ethers 4 was next examined. In entry 2, the addition of 4a resulted in the reversal of the selectivity, i.e., a 3:1 preference for the cis isomer 2a. This results indicated that the iodocyclization occurred via the corresponding silyl ether of 1a. During the screening of silyl enol ethers (entries 2 5), trimethylsiloxy cyclohexene 4d gave the best result with a 88% combined yield and 11:1 selectivity. For enhancement of the selectivity, more bulky triethylsilyl (TES) derivative 4e was used.
However, the selectivity was not improved (entry 6). The TMS group proved to be bulky enough for any steric effect on the present reaction. Other common solvents for the halocyclization, such as acetonitrile and THF, gave poor results (entries 7 and 8).10 N-Bromosuccinimide (NBS) was not effective for this reaction because the siloxy intermediate was not formed (entry 9). Compounds 2b and 3b were formed directly from 1a due to the low reactivity of NBS toward the silyl enol ether. With the optimized conditions in hand, we then explored the generality and scope of the substrates using various γ,δ-unsaturated alcohols 1 (Table 2). In entries 1 3, the reaction of alcohols 1b d smoothly proceeded to predominantly give the cis products 2b d. The alcohols with various functional groups 1e g were available for this reaction, and the corresponding products 2e g were obtained in high yields without any difficulty (entries 4 6). It is noteworthy that acidlabile tert-butyldimethylsilyl (TBS) and triphenylmethyl (Tr) groups were not affected under these conditions (entries 5 and 6). Even using the substrates with internal olefins 1h and 1i, the stereoselective cyclization proceeded diastereoselectively in high yields (entries 7 and 8).
Table 2. Iodocyclization of γ,δ-Unsaturated Alcohol 1a
Table 1. Optimizationa
a Unless otherwise noted, reactions were performed using silyl enol ether (1.5 equiv) and NIS (2.5 equiv). b Total yields of 2 and 3. c Dr was determined by 1H NMR. d 1.5 equiv of NIS was used. e NBS was used instead of NIS.
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a Unless otherwise noted, reactions were performed using 4d (1.5 equiv) and NIS (2.5 equiv). b Dr was determined by 1H NMR. c Reactions were performed at 40 °C.
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In accord with Bartlett’s proposal,7 a plausible explanation for the reaction mechanism of the present iodocyclization is exemplified in Scheme 1 using alcohol 1a and silyl enol ether 4d. Initially, 4d was activated by NIS and reacted with 1a to give the intermediate 6 and coproduct 5.11 The minor product 3a should be generated through the highenergy transition states due to 1,2-steric interactions. As a result, cis-2,5-THF 2a was favorably obtained.
Scheme 1. Plausible Reaction Mechanism
to bis-THFs with a cis/threo/cis relative stereochemistry was rather limited.13 We planned the one-pot synthesis of adjacent bis-THFs using our method. As illustrated in Scheme 3, the double iodocyclization of C2-symmetric diol 8, which is readily obtained from trans-1,5,9-decatriene by the regioselective Sharpless asymmetric dihydroxylation,14 produced cis/threo/cis bis-THF 9 in an 83% combined yield with a 9:1 selectivity.15 In the absence of 4d, the double iodocyclization favorably produced the trans/threo/trans isomer.16 These results indicated that the formation of the newly formed stereogenic centers can be controlled by the presence or absence of silyl enol ether 4d.
Scheme 3. One-Pot Synthesis of cis/threo/cis Bis-THF 9
To demonstrate the utility of our products, we performed the substitution of the iodine atom in 2a. Upon treatments of 2a with sodium azide, sodium thiophenolate and sodium cyanide, the corresponding substituted compounds 7a c were obtained in good yields (Scheme 2).
Scheme 2. Derivatization of 2a
Adjacent bis-THF fragments are essential components of Annonaceous acetogenins, which show a wide array of biological properties such as antitumor, immunosuppresive, antimicrobial and insecticidal activities.1,12 Although many methods have been developed for the synthesis of the bis-THF cores of Annonaceous acetogenins, the approach (9) There are some reports for the iodocyclization of silyl ethers, though in rather low yields or low selectivity. (a) Reference 7. (b) Brimble, A. M.; Edmonds, K. M. Tetrahedron 1995, 51, 9995. (10) Details of optimization are provided in the Supporting Information. (11) We isolated compound 6 and coproduct 5 and confirmed their structures by 1H NMR (see the Supporting Information). (12) For a recent review for total synthesis of Annonaceous acetogenins, see: Li, N.; Shi, Z.; Tang, Y.; Chen, J.; Li, X. Beilstein J. Org. Chem. 2008, 4, 48. 1056
Next, the obtained 9 was converted into the cis/threo/cis bis-THF cores of Annonaceous acetogenins, which are found in rolliniastatin 1, rollimembrin, and membranacin.17 In a previous synthetic route to these natural products, the stereocenters in bis-THF cores are constructed in order and many reaction steps are required.13c f Although Piccialli reported an elegant one-pot synthesis of bis-THF rings from linear polyenes by oxidative cyclization, the product yields were low.13g,h We aimed at the concise synthesis of Koert and Lee’s common intermediate 1313c,e for the synthesis of the set of natural products, rolliniastatin 1, rollimembrin, and membranacin (Scheme 4). The substitutions of two iodine atoms in 9 by sodium (13) (a) Bruke, S. D.; Jiang, L. Org. Lett. 2001, 3, 1953. (b) Wysocki, L. M.; Dodge, M. W.; Voight, E. A.; Bruke, S. D. Org. Lett. 2006, 8, 5637. (c) Koert, U. Tetrahedron Lett. 1994, 35, 2517. (d) Head, G. D.; Whittingham, W. G.; Brown, R. C. D. Synlett 2004, 1437. (e) Keum, G.; Hwang, C. H.; Kang, S. B.; Kim, Y.; Lee, E. J. Am. Chem. Soc. 2005, 127, 10396. (f) Morris, C. L.; Hu, Y.; Head, G. D.; Brown, L. J.; Whittingham, W. G.; Brown, R. C. D. J. Org. Chem. 2009, 74, 981. (g) Bifulco, G.; Caserta, T.; Gomez-Paloma, L.; Piccialli, V. Tetrahedron Lett. 2002, 43, 9265. (h) Piccialli, V.; Caserta, T.; Caruso, L.; GomezPaloma, L.; Bifulco, G. Tetrahedron 2006, 62, 10989. (14) Diol 8 was prepared from commercially available trans-1,5, 9-decatriene in one step (57% yield).Tian, S.-K.; Wang, Z.-M.; Jiang, J.-K.; Shi, M. Tetrahedron: Asymmetry 1999, 10, 2551. (15) The ratio of two diastereomers was determined by 1H NMR. Two diasteromers were inseparable and 9 (9:1 dr) was used for further transformation in Scheme 4. (16) The iodocyclization of ent-8 with iodine gave trans/threo/trans bis-THF product as a major isomer with a 7:1 selectivity: Lee, S.; Lee, Y.-S.; Park, G.; Choi, S.; Yoon, S.-H. Bull. Korean Chem. Soc. 1998, 19, 115. (17) (a) Pettit, G. R.; Cragg, G. M.; Polonsky, J.; Herald, D. L.; Goswami, A.; Smith, C. R.; Moretti, C.; Schmidt, J. M.; Weisleder, D. Can. J. Chem. 1987, 65, 1433. (b) Gonzalez, M. C.; Tormo, J. R.; Bermejo, A.; Zafra-Polo, M. C.; Estornell, E.; Cortes, D. Bioorg. Med. Chem. Lett. 1997, 7, 1113. (c) Saez, J.; Sahpaz, S.; Villaescusa, L.; Hocquemiller, R.; Cave, A. J. Nat. Prod. 1993, 56, 351. (d) Chavez, D.; Acevedo, L. A.; Mata, R. J. Nat. Prod. 1999, 62, 1119. (e) Gonzalez, M. C.; Lavaud, C.; Gallardo, T.; Zafra-Polo, M. C.; Cortes, D. Tetrahedron 1998, 54, 6079. Org. Lett., Vol. 14, No. 4, 2012
Scheme 4. Application to Natural Products Synthesis
thiophenolate gave 10. Oxidation of thiol, Pummerer rearrangement of sulfoxide, and reduction of aldehyde (18) Aldehyde 13 was obtained as an inseparable mixture of two diastereomers (9:1 dr). The major diastereomer was identical with the Koert and Lee’s common intermediate 13. The undesired isomer is separable when the diol 11 is transformed into the corresponding TBDPS-ether 14 (see the Supporting Information).
afforded diol 11. The expedient synthesis of compound 13 was achieved via the monoprotection of the hydroxyl groups and subsequent oxidation of the remained alcohol with Dess-Martin periodinane. Consequently, we accomplished the synthesis of the key intermediate 13 from the known diol 8 in seven steps with a 56% overall yield.18 In conclusion, we have described the efficient and concise synthesis of cis-2,5-disubstituted THFs from γ,δ-unsaturated alcohols. Our report is the first example of the selective synthesis of a cis-2,5-THF stereoisomer from the alcohol precursors in a one-pot procedure by an iodocyclization strategy. The present method is applicable to various substrates with acid-sensitive functions and internal olefins. We have achieved the efficient formation of adjacent bis-THFs with a cis/threo/cis stereochemistry, which are an essential component of some Annonaceous acetogenins. We have also disclosed the useful utilization of a halogenating reagent in organic synthesis. Acknowledgment. This work was supported by Grant-inAid for Scientific Research from the Japan Society for the Promotion of Science (JSPS). K.N. acknowledges a Research Fellowship for Young Scientists from JSPS. Supporting Information Available. Experimental details and detailed spectroscopic data of all new compounds including TBDPS-ether 14. This material is available free of charge via the Internet at http://pubs. acs.org. The authors declare no competing financial interest.
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